Antiplatelet activity of carvedilol in comparison to propranolol

Abstract

The non-selective vasodilating beta-blocker carvedilol was found to inhibit platelet aggregation as well as thromboxane B(2) formation more effectively than propranolol. The antiaggregatory activity of carvedilol decreased, depending on the stimulus used, in the following rank order of potency (in parentheses the respective mean inhibitory concentrations of carvedilol and propranolol are given in micromol/l): PMA (19 and 34) > thrombin (55 and 77) > Ca(2+)-ionophore A23187 (58 and 81) > epinephrine (86 and 118). However, aggregation of platelets activated with ADP was not affected by carvedilol in concentrations up to 100 micromol/l. In platelets stimulated with thrombin, carvedilol (10 micromol/l) reduced thromboxane B(2) formation by 64%, whereas propranolol was ineffective at this concentration. Moreover, A23187-induced formation of thromboxane B(2), not affected by propranolol, was completely blocked by 100 micromol/l carvedilol. In comparison to propranolol, the molecule of carvedilol is more lipophilic and possesses lower dipole moment and higher molar refractivity, thus penetrating into platelet membranes readily and in large quantities. The antiplatelet effect was assumed to result from interactions of carvedilol with membrane macromolecules (phospholipids, ion channels, enzymes, etc.) rather than from blockade of alpha- and beta-adrenergic receptors.

In vitro Effect of Carvedilol on Professional Phagocytes

“…Since it affected superoxide generation in a similar way after both stimuli only in higher concentrations, its effect seems to be of non-receptor type. Physicochemical properties of carvedilol (partition coefficient, dipole moment, and high lipophilicity) and its antiplatelet activity [21] support this conclusion.…”

“…The comparable inhibitory effect on plant (HRP) and human (MPO) enzyme, yet less pronounced than its effect on MPO release from intact cells, indicates the possibility that carvedilol similarly to other lipophilic ␤ -adrenoceptor-blocking drugs [21,26] interferes with membrane structure, influencing predominantly phospholipid metabolism. Carvedilol may directly affect enzymes by uncoupling/chelating iron ions [11,27,28] or indirectly as a lipophilic molecule readily entering into the non-polar parts of membranes and causing membrane disordering as was shown for artificial membranes/ liposomes [29] .…”

“…Carvedilol may directly affect enzymes by uncoupling/chelating iron ions [11,27,28] or indirectly as a lipophilic molecule readily entering into the non-polar parts of membranes and causing membrane disordering as was shown for artificial membranes/ liposomes [29] . Interaction with membrane rather than an adrenoceptor-blocking effect has been suggested to be involved in the antiaggregatory activity of carvedilol [21] . The higher inhibitory effect of carvedilol (100 mol/l decreased the CL signal to approximately 30% of the control value) on crude extract of MPO from HL-60 measured by means of CL, in comparison to human neutrophil MPO and HRP measured by means of spectrophotometry, involves its antioxidative/scavenging activities.…”

Antiplatelet and Antileukocyte Effects of Cardiovascular,Immunomodulatory and Chemotherapeutic Drugs

“…There were no species differences in the inhibition of platelet aggregation induced by -blockers in vitro. Experiments with human, rat, rabbit or canine platelets showed similar results [8][9][10][11][12][13].…”

Anti-thrombotic effects of nebivolol and carvedilol: Involvement of β2 receptors and COX-2/PGI2 pathways

“…In contrast to the 32 numerous reports on the effects of third generation beta- 33 adrenergic antagonists on NO-dependent function, including 34 reports documenting their ability to reverse the impairment of 35 NO-dependent endothelial function in humans [22][23][24][25][26][27], little is 36 known on the ability of carvedilol and nebivolol to modulate PGI 2 -37 dependent endothelium functions. Interestingly, antiplatelet 38 effects of nebivolol [28,29] and carvedilol [30] were demonstrated, 39 but the involvement of PGI 2 in these effects was not investigated. 40 In the present work, we studied the anti-thrombotic effects of 41 nebivolol and carvedilol, and in particular, the role of beta-2 42 adrenoceptors in the anti-thrombotic PGI 2 -dependent responses 43 induced by nebivolol or carvedilol.…”